Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma that remains incurable due to the development of drug resistance, despite the plethora of therapies available. Each successive treatment failure is associated with a more rapidly proliferating disease and fewer practical treatment options. For example, the BTK inhibitor (BTKi) ibrutinib initially has unprecedented efficacy, but failure is virtually universal and is associated with dismal outcomes. Understanding the genomic basis and mechanisms for drug resistance in MCL is therefore urgently needed. Our goal is to develop superior therapies for MCL that are effective, durable, well tolerated and amenable to patient stratification, by defining the genomic and molecular mechanisms for drug resistance. Targeting the cell cycle represents a rational approach to MCL therapy, as dysregulation of CDK4 and cyclin D1 expression underlie unrestrained proliferation in disease progression. We have demonstrated that induction of prolonged early G1 arrest (pG1) by inhibiting CDK4 with palbociclib not only prevents proliferation of primary MCL cells but also reprograms them for killing by clinically relevant targeting agents including ibrutinib and PI3K inhibitors (PI3Ki)s. Longitudinal functional genomics of serial biopsies from MCL patients treated with either palbociclib or ibrutinib further uncovered a close association between clinical response and inactivation of PI3K as well as activation of the tumor suppressor transcription factor FOXO1. Moreover, chromatin remodeling appeared to be the proximal event that reprograms MCL cells in response to CDK4 inhibition. Collectively, our findings suggest that through regulation of PI3K, FOXO1 and the epigenome, induction of pG1 by CDK4 inhibition reprograms MCL for a deeper, more durable clinical response to BTKi and PI3Ki. Supporting this hypothesis, in our phase 1 clinical trial of palbociclib + ibrutinib (PALIBR) in recurrent MCL, the overall response rate was 67% with 43% complete responses. The responses were rapid and durable; only 2 responding patients have progressed in the 32 months since the trial opened. To further accelerate the development of targeted MCL therapies, we have developed a novel inhibitor for protein arginine methyl transferase 5 (PRMT5), which is dysregulated in MCL and many other human cancers. Inhibition of PRMT5 reverses PRMT5-catalyzed epigenetic marks, restores regulatory pathways and kills ibrutinib-resistant primary MCL cells. Building on these novel findings and capitalizing on the upcoming multi-center phase 2 PALIBR in recurrent MCL, we propose to achieve our goals with three integrated specific aims: 1) to define the mechanism for clinical response to targeting CDK4 in combination therapy and identify the resistance genomic markers; 2) to determine the role of FOXO1 and chromatin remodeling in cell cycle therapy; and 3) to target PRMT5 in MCL. Collectively, the tools and knowledge assembled from these innovative and timely studies should significantly advance therapeutic targeting of the cell cycle and the epigenome in MCL and provide new insights into the mechanism of drug resistance in MCL and beyond.